Maternal gut microbiota in fetal programming of neurodevelopment and related disorders

母体肠道微生物群在胎儿神经发育和相关疾病编程中的作用

• 批准号: 10668634
• 负责人: Shelly A Buffington
• 金额: $ 56.66万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668634
• 关键词: ATAC-seq; Adoptive Transfer; Adverse effects; Affect; Behavior; Behavior assessment; Behavioral; Behavioral Symptoms; Brain; Brain region; Businesses; CD4 Positive T Lymphocytes; Cell Maturation; Cell Separation; Chronic Disease; Consensus; Coupled; Data; Development; Diet; Disease; Disease susceptibility; Embryo; Environmental Risk Factor; Epigenetic Process; Exposure to; Family; Female; Fetal Development; Functional disorder; Generations; Genetic Predisposition to Disease; Germ-Free; Goals; Health; High Fat Diet; Human; Hypothalamic structure; Immune; Impairment; Individual; Industrialization; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interdisciplinary Study; Intervention; Life; Mediating; Metabolic syndrome; Metagenomics; Mus; Neurodevelopmental Deficit; Neurodevelopmental Disorder; Outcome; Pathologic; Pathology; Pathway interactions; Peptide Initiation Factors; Personal Satisfaction; Phenotype; Physiology; Population; Predisposition; Pregnancy; Probiotics; Process; Rag1 Mouse; Recovery; Reporting; Rewards; Schizophrenia; Serum; Social Behavior; Social Interaction; Synaptic plasticity; Testing; Therapeutic; Volatile Fatty Acids; Whole-Genome Shotgun Sequencing; Work; antenatal care; associated symptom; autism spectrum disorder; cell type; critical period; cytokine; discrete time; dysbiosis; experience; fecal transplantation; fetal; fetal programming; gastrointestinal symptom; gut dysbiosis; gut microbiome; gut microbiota; immune activation; immune function; imprint; improved; in utero; insight; male; maternal microbiome; metabolome; metabolomics; microbial; microbiome; microbiome composition; microbiota transplantation; neural circuit; neurobehavioral; neurodevelopment; neuroinflammation; neuropathology; neuropsychiatric disorder; neuropsychiatry; offspring; patient population; prenatal exposure; prevent; sex; sexual dimorphism; social; social deficits; therapeutic target; transcriptome sequencing

Project Summary Social interaction is fundamental to the most universal of human experiences, such as family life, business, and romance; however, social dysfunction is a debilitating hallmark of major neurodevelopmental disorders, including autism and schizophrenia. Despite significant advances, the mechanisms underlying social dysfunction and other core behavioral symptoms associated with neurodevelopmental disorders remain elusive and interventions limited. There is growing consensus in support of a ‘two hit’ hypothesis for neurodevelopmental disorders, in which a secondary environmental factor initiates abnormal developmental programming that contributes to behavioral dysfunction in genetically predisposed individuals. Among environmental factors, diet is a leading factor contributing to host disease susceptibility. Notably, diet is the chief determinant of host gut microbiome composition. Through modulation of host immune function, and even the brain and behavior, the gut microbiome is emerging as a major influence on host health and well-being. Disruption, or ‘dysbiosis,’ of the gut microbiome is, in turn, associated with several common inflammatory disorders, including inflammatory bowel disease and metabolic syndrome. Dysbiosis is also observed in neuropsychiatric patient populations, who have a high rate of gastrointestinal symptom comorbidity; yet, the relationship between dysbiosis of the gut microbiome and neurodevelopmental or other neuropsychiatric disorders is poorly understood. In this project, we will determine if maternal high-fat diet (MHFD)-induced dysbiosis of the gut microbiome during pregnancy contributes to descendant neurobehavioral dysfunction and the underlying mechanisms. Previously, we reported that MHFD induces dysbiosis of the male offspring gut microbiome as well as social dysfunction and underlying deficits in synaptic plasticity in the social reward circuit. Recently, we identified a sexually dimorphic effect of MHFD on offspring behavior–stronger social deficits are evident in males versus females–however, we observed dysbiosis of both the male and female MHFD offspring gut. We reasoned that if the maternal gut microbiome is causally related to offspring social dysfunction, then enduring dysbiosis of the female MHFD offspring gut microbiome in the F1 generation may be sufficient to impair neurodevelopment and behavior in F2 males. Indeed, we observed robust social dysfunction in male, but not female, F2 offspring. Here, we will test the hypothesis that HFD-induced dysbiosis of the maternal gut microbiome drives abnormal fetal programming in F1 offspring that underlies social dysfunction in both F1 and F2 males. In Aim 1, we will ask how HFD/MHFD affects remodeling of the P/F1 maternal gut microbiome during pregnancy. In Aim 2, we will determine the effects of HFD/MHFD on maternal immune function, fetal immune imprinting, and the embryonic brain. In Aim 3, we will determine if modulation of the maternal gut microbiome during pregnancy can rescue descendant social dysfunction. This study will yield key insight into the mechanisms by which MHFD modulates fetal development and the potential for therapeutic targeting of the maternal microbiome to prevent adverse neurobehavioral outcomes in descendant generations.

项目概要 社交互动是最普遍的人类经历的基础，例如家庭生活、商业和生活 然而，社交功能障碍是主要神经发育障碍的一个令人衰弱的标志，包括 尽管自闭症和精神分裂症取得了重大进展，但社会功能障碍和潜在的机制仍然存在。 与神经发育障碍相关的其他核心行为症状仍然难以捉摸且干预措施 越来越多的人一致支持神经发育障碍的“两次打击”假说。 次要环境因素引发异常的发育编程，从而导致 在遗传易感个体的行为功能障碍中，饮食是主要的环境因素。 导致宿主疾病易感性的因素值得注意的是，饮食是宿主肠道微生物群的主要决定因素。 通过调节宿主免疫功能，甚至大脑和行为、肠道微生物组。 肠道微生物组的破坏或“生态失调”正在成为对宿主健康和福祉的主要影响。 反过来，与几种常见的炎症性疾病有关，包括炎症性肠病和 在神经精神科患者群体中也观察到代谢失调，其发病率很高。 然而，肠道微生物群失调与胃肠道症状合并症之间的关系； 我们对神经发育或其他神经精神疾病知之甚少。 怀孕期间母亲高脂饮食 (MHFD) 引起的肠道微生物群失调是否会导致 此前，我们报道了 MHFD 的后代神经行为功能障碍及其潜在机制。 引起雄性后代肠道微生物组的失调以及社会功能障碍和潜在的缺陷 最近，我们发现了 MHFD 对性别二态性的影响。 后代行为——与女性相比，男性明显存在更严重的社会缺陷——然而，我们观察到生态失调 我们推断，如果母体肠道微生物组是因果关系的话。 与后代社会功能障碍有关，然后女性 MHFD 后代肠道微生物群的持久失调 事实上，我们观察到，F1 代可能足以损害 F2 雄性的神经发育和行为。 F2 后代中雄性（而非雌性）存在强烈的社会功能障碍。在这里，我们将检验 HFD 引起的假设。 母体肠道微生物组的失调导致 F1 后代的胎儿编程异常，这是社会性的基础 F1 和 F2 雄性的功能障碍 在目标 1 中，我们将询问 HFD/MHFD 如何影响 P/F1 的重塑。 在目标 2 中，我们将确定 HFD/MHFD 对母体的影响。 在目标 3 中，我们将确定免疫功能、胎儿免疫印记和胚胎大脑是否受到调节。 怀孕期间母体肠道微生物组可以挽救后代的社会功能障碍。 对 MHFD 调节胎儿发育的机制以及治疗潜力的关键见解 以母体微生物群为目标，防止后代出现不良神经行为后果。